男性不育与POLG基因CAG-三核苷酸重复的相关性研究
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摘要
全世界已婚孕龄夫妇存在生育困难的发病率高达10%-15%,男女因素大约各占50%。目前普遍认为精子功能缺陷是造成男性不育的最主要原因之一。精子活力是衡量精液质量和男性生育力的一项重要指标。炎症、免疫因素、理化因子等均会导致精子活力降低,其中能量障碍为一个重要原因,ATP是精子活力的首要能量来源,精子需要位于其尾部中段的线粒体氧化呼吸链提供ATP维持精子的活力和生育能力。线粒体DNA突变可影响ATP生成,从而直接或间接影响精子活力,进而引起精子发生障碍或弱精子症。DNA聚合酶γ(DNA po1ymerase gamma,polγ)是在mtDNA的复制和修复中起重要作用的核酶,并被认为是线粒体中唯一起聚合酶作用的酶。POLG基因的突变将会影响polγ的复制、校正活性,可能导致线粒体基因组的突变并最终影响ATP的产生。人类polγ在N端编码区出现CAG-三核苷酸重复序列,这个序列基因包含10个连串的编码Gln的CAG密码子。迄今为止,已发现POLG基因CAG-三核苷酸重复与人类疾病相关,如帕金森综合症、亨廷顿舞蹈症等,因此科学家们推测POLG基因区域的重复长度多态性可以作为评价基因在人类疾病中的作用的一个十分有用的标志。
目前有很多关于POLG基因CAG-三核苷酸重复与男性不育相关性的研究,但是不同人群的研究得到的却是不一致的结果。因此,本课题研究中国人群男性不育与POLG基因CAG-三核苷酸重复的相关性,并试图得出男性不育与POLG基因CAG-三核苷酸重复相关性的确切结论。本课题同时开展中国不同群体POLG基因CAG-三核苷酸重复分布的检测和男性不育病例组和对照组POLG基因CAG-三核苷酸重复的关联性研究,然后运用Meta分析并结合得到的群体分布结果和病例-对照研究的数据,综合分析男性不育与POLG基因CAG-三核苷酸重复的相关性。一方面,我们对中国6个不同地区的汉族群体的健康个体进行POLG基因CAG-三核苷酸重复基因分型,以得到中国汉族人群POLG基因CAG-三核苷酸重复的分布情况,为男性不育与POLG基因CAG-三核苷酸重复相关性研究提供中国汉族人群的基因背景。同时对中国不同少数民族群体(独龙族、佤族、傈僳族、怒族、白族、撒拉族、藏族、土族、蒙古族和哈尼族爱伲人)的健康个体进行POLG基因CAG-三核苷酸重复基因分型,观察各民族群体中POLG基因CAG-三核苷酸重复的分布特点。另一方面,对367例少／弱精症男性不育患者和323例健康可育正常对照进行POLG基因CAG-三核苷酸重复基因分型,通过病例对照研究分析中国人群少/弱精症男性不育与POLG基因CAG-三核苷酸重复的相关性。最终,通过对比不同群体间POLG基因CAG-三核苷酸重复分布的差异,同时搜集现有报道的关于男性不育与POLG基因CAG-三核苷酸重复相关性的病例对照研究文献设计一个Meta分析,以综合评价POLG基因CAG-三核苷酸重复在男性不育发病中的作用,并分析各项研究间产生不一致结论的原因。
我们的研究结果显示：
中国各群体最普遍的POLG等位基因是(CAG)10,各群体间最主要的POLG基因型为10/10；6个不同地区的汉族群体最主要的突变基因型为10/11,各少数民族最主要的突变基因型为9/10和10/11；在所研究的6个汉族群体中均未发现有POLG基因突变纯合子(not10/not10),而在少数民族群体中检测到POLG基因突变纯合子(not10/not10):独龙族6/6、沧源佤族11/11。在6个不同地区的汉族群体中POLG基因CAG-等位基因频率和基因型频率分布差异没有统计学意义,但是汉族群体与独龙族、沧源佤族、哈尼族爱伲人、撒拉族、福贡怒族、西藏藏族和贡山怒族等群体的等位基因频率分布的差异均有统计学意义,研究的各少数民族群体间的等位基因频率分布差异也有统计学意义。在世界范围内比较发现,各不同种族、民族群体POLG基因CAG-三核苷酸重复的分布有显著差异。
病例、对照组POLG基因CAG-三核苷酸重复等位基因的分型结果显示,正常对照组和男性不育组中最常见都是(CAG)10等位基因,频率分别为：病例组97.96%,对照组97.52%,POLG基因CAG-三核苷酸重复数在病例组中分布为7、9、10、11和12,对照组中的分布为9、10、11和13。男性不育组和正常对照组最主要的POLG基因型为10/10,该基因型频率分别为：病例组96.46%,对照组95.05%。统计结果显示：病例组和对照组POLG CAG-等位基因和基因型频率分布差异无统计学意义(P=0.588,OR=0.821,95％CI:0.403-1.675和P=0.357,OR=O.705.95％CI:0.334-1.488).我们的结果提示,中国人群男性不育与POLG基因CAG-三核苷酸重复不相关。
基于我们的研究结果,我们搜集现有关于男性不育与POLG基因CAG-三核苷酸重复相关性的病例对照研究报道数据,构建了一个较为周密详尽的Meta分析。本次Meta分析纳入了包括本研究在内的10项相关研究文献,共计包含2680例男性不育病例和1677例正常对照,采用多种遗传比较模式(杂合子比较、纯合子比较、隐性遗传比较、显性遗传比较)对男性不育病例组和正常对照组间POLG基因CAG-三核苷酸重复的分布频率进行定量的综合分析。综合分析研究结果发现,男性不育与POLG基因CAG-三核苷酸重复没有相关性。
我们的研究提示,POLG基因CAG-三核苷酸重复的分布在不同群体间存在较大的不同,中国汉族群体的(CAG)10等位基因频率和10/10基因型频率高于其它群体的频率分布,并且各群体间突变型等位基因和基因型的分布也有差异,我们研究的病例和对照组的频率分布与中国汉族群体的频率分布相符,但差异没有统计学意义。Meta分析显示,男性不育与POLG基因CAG-三核苷酸重复没有相关性。基于以上结果,我们推测,①不同群体间POLG基因CAG-三核苷酸重复分布的遗传背景差异影响着该群体与男性不育的相关性,②POLG基因CAG-三核苷酸的重复次数在不同群体可能有不同的变异范围,超出变异范围的重复次数可能导致疾病的发生,而并非所有变异的重复次数都与疾病的发生相关,③POLG基因CAG-三核苷酸的重复可能只是男性不育的一个微效基因,可能它与基因调控网络中的其它位点相互作用与男性不育相关。因此,我们提出,POLG基因CAG-三核苷酸的重复并不是男性不育易感性的关键位点。但是,鉴于polγ的重要功能,在今后的关于男性不育遗传相关性的研究可考虑从与POLG基因调控相关联的其它基因(如线粒体DNA等)入手,通过基因间的相互作用研究基因与男性不育的相关性。
Male infertility is a multi-factorial syndrome encompassing a wide variety of disorders. Approximately 15 percent of couples are infertile, and among these couples, male factor infertility accounts for approximately 50 percent of causes. DNA polymerase y (POLG), which is encoded by the POLG gene, is the only known DNA polymerase for mtDNA replication and maintenance in human beings. The human POLG gene is located on 15q24-15q26, spans 23 exons, and includes a trinucleotide CAG-repeat region which encodes a polyglutamine stretch near the N-terminus of the mature protein and downstream of the presumed mitochondrial targeting sequence. It has been reported that human cDNA sequences contain 10 consecutive glutamines encoding CAG codons, followed by a single glutamine encoding a CAA codon, and two further CAG codons. Polyglutamine tracts can be sites of protein-protein interactions; altering the tract in POLG may result in suboptimal or improper mtDNA replication. To date over 150 disease mutations and 9 nonsynonymous polymorphisms in POLG have been found to be associated with autosomal recessive and dominant diseases.
Meta-analysis is a statistical method of large collection of analysis results from individual studies for the purpose of integrating the findings. Meta-analysis enable us to report that the effect is robust across the kinds of populations sampled, and also to estimate the magnitude of the effect more precisely than we could with any of the studies alone.
Several reports have implicated a association between the length of CAG-repeat in the polymerase y gene (pol y) and male infertility. However, such results have not been reproduced in other studies. In the present study, POLG-CAG repeat were analyzed in 535 healthy individuals from 6 Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were 97.38% and 94.13%respectively; however, there was no significant difference among the 6 Chinese Han populations. We performed a pairwise comparison of different populations previously published on the frequency of the CAG-repeats genotype and found differences in the frequency of the three POLG CAG-repeats genotype between geographically-and ethnically-related populations. The prevalence of homozygous wild type (10/10) was shown to be exceedingly high in Chinese (97.38%). These results indicated that there is a significant difference in frequencies of the three CAG-repeat genotypes among different populations. Further, we determined the distribution of POLG-CAG repeat in 367 infertile men and 323 fertile men. Our study suggested that the distribution of POLG-CAG repeat alleles and genotypes were not significantly different between infertile (95.67%and 92.67%) and fertile men (97.22%and 94.44%). In a subsequent Meta-analysis combining our data with previous studies, a comparison of CAG-repeat alleles showed there was no obvious association with male infertility (pooled OR=0.94; 95%CI:0.60-1.48). The lack of significance appeared after combined genotypes with the following genetic models: homozygote comparison, heterozygote comparison, dominant model comparison, and recessive genetic comparison. In conclusion, the frequencies of POLG CAG-repeat variants are quite different in diverse ethnicities and this polymorphism may not be associated with Chinese male infertility. Based on a subsequent Meta-analysis, there was no obvious association between CAG-repeat variants of the POLG gene and male infertility.
目前有很多关于POLG基因CAG-三核苷酸重复与男性不育相关性的研究,但是不同人群的研究得到的却是不一致的结果。因此,本课题研究中国人群男性不育与POLG基因CAG-三核苷酸重复的相关性,并试图得出男性不育与POLG基因CAG-三核苷酸重复相关性的确切结论。本课题同时开展中国不同群体POLG基因CAG-三核苷酸重复分布的检测和男性不育病例组和对照组POLG基因CAG-三核苷酸重复的关联性研究,然后运用Meta分析并结合得到的群体分布结果和病例-对照研究的数据,综合分析男性不育与POLG基因CAG-三核苷酸重复的相关性。一方面,我们对中国6个不同地区的汉族群体的健康个体进行POLG基因CAG-三核苷酸重复基因分型,以得到中国汉族人群POLG基因CAG-三核苷酸重复的分布情况,为男性不育与POLG基因CAG-三核苷酸重复相关性研究提供中国汉族人群的基因背景。同时对中国不同少数民族群体(独龙族、佤族、傈僳族、怒族、白族、撒拉族、藏族、土族、蒙古族和哈尼族爱伲人)的健康个体进行POLG基因CAG-三核苷酸重复基因分型,观察各民族群体中POLG基因CAG-三核苷酸重复的分布特点。另一方面,对367例少／弱精症男性不育患者和323例健康可育正常对照进行POLG基因CAG-三核苷酸重复基因分型,通过病例对照研究分析中国人群少/弱精症男性不育与POLG基因CAG-三核苷酸重复的相关性。最终,通过对比不同群体间POLG基因CAG-三核苷酸重复分布的差异,同时搜集现有报道的关于男性不育与POLG基因CAG-三核苷酸重复相关性的病例对照研究文献设计一个Meta分析,以综合评价POLG基因CAG-三核苷酸重复在男性不育发病中的作用,并分析各项研究间产生不一致结论的原因。
我们的研究结果显示：
中国各群体最普遍的POLG等位基因是(CAG)10,各群体间最主要的POLG基因型为10/10；6个不同地区的汉族群体最主要的突变基因型为10/11,各少数民族最主要的突变基因型为9/10和10/11；在所研究的6个汉族群体中均未发现有POLG基因突变纯合子(not10/not10),而在少数民族群体中检测到POLG基因突变纯合子(not10/not10):独龙族6/6、沧源佤族11/11。在6个不同地区的汉族群体中POLG基因CAG-等位基因频率和基因型频率分布差异没有统计学意义,但是汉族群体与独龙族、沧源佤族、哈尼族爱伲人、撒拉族、福贡怒族、西藏藏族和贡山怒族等群体的等位基因频率分布的差异均有统计学意义,研究的各少数民族群体间的等位基因频率分布差异也有统计学意义。在世界范围内比较发现,各不同种族、民族群体POLG基因CAG-三核苷酸重复的分布有显著差异。
病例、对照组POLG基因CAG-三核苷酸重复等位基因的分型结果显示,正常对照组和男性不育组中最常见都是(CAG)10等位基因,频率分别为：病例组97.96%,对照组97.52%,POLG基因CAG-三核苷酸重复数在病例组中分布为7、9、10、11和12,对照组中的分布为9、10、11和13。男性不育组和正常对照组最主要的POLG基因型为10/10,该基因型频率分别为：病例组96.46%,对照组95.05%。统计结果显示：病例组和对照组POLG CAG-等位基因和基因型频率分布差异无统计学意义(P=0.588,OR=0.821,95％CI:0.403-1.675和P=0.357,OR=O.705.95％CI:0.334-1.488).我们的结果提示,中国人群男性不育与POLG基因CAG-三核苷酸重复不相关。
基于我们的研究结果,我们搜集现有关于男性不育与POLG基因CAG-三核苷酸重复相关性的病例对照研究报道数据,构建了一个较为周密详尽的Meta分析。本次Meta分析纳入了包括本研究在内的10项相关研究文献,共计包含2680例男性不育病例和1677例正常对照,采用多种遗传比较模式(杂合子比较、纯合子比较、隐性遗传比较、显性遗传比较)对男性不育病例组和正常对照组间POLG基因CAG-三核苷酸重复的分布频率进行定量的综合分析。综合分析研究结果发现,男性不育与POLG基因CAG-三核苷酸重复没有相关性。
我们的研究提示,POLG基因CAG-三核苷酸重复的分布在不同群体间存在较大的不同,中国汉族群体的(CAG)10等位基因频率和10/10基因型频率高于其它群体的频率分布,并且各群体间突变型等位基因和基因型的分布也有差异,我们研究的病例和对照组的频率分布与中国汉族群体的频率分布相符,但差异没有统计学意义。Meta分析显示,男性不育与POLG基因CAG-三核苷酸重复没有相关性。基于以上结果,我们推测,①不同群体间POLG基因CAG-三核苷酸重复分布的遗传背景差异影响着该群体与男性不育的相关性,②POLG基因CAG-三核苷酸的重复次数在不同群体可能有不同的变异范围,超出变异范围的重复次数可能导致疾病的发生,而并非所有变异的重复次数都与疾病的发生相关,③POLG基因CAG-三核苷酸的重复可能只是男性不育的一个微效基因,可能它与基因调控网络中的其它位点相互作用与男性不育相关。因此,我们提出,POLG基因CAG-三核苷酸的重复并不是男性不育易感性的关键位点。但是,鉴于polγ的重要功能,在今后的关于男性不育遗传相关性的研究可考虑从与POLG基因调控相关联的其它基因(如线粒体DNA等)入手,通过基因间的相互作用研究基因与男性不育的相关性。
Male infertility is a multi-factorial syndrome encompassing a wide variety of disorders. Approximately 15 percent of couples are infertile, and among these couples, male factor infertility accounts for approximately 50 percent of causes. DNA polymerase y (POLG), which is encoded by the POLG gene, is the only known DNA polymerase for mtDNA replication and maintenance in human beings. The human POLG gene is located on 15q24-15q26, spans 23 exons, and includes a trinucleotide CAG-repeat region which encodes a polyglutamine stretch near the N-terminus of the mature protein and downstream of the presumed mitochondrial targeting sequence. It has been reported that human cDNA sequences contain 10 consecutive glutamines encoding CAG codons, followed by a single glutamine encoding a CAA codon, and two further CAG codons. Polyglutamine tracts can be sites of protein-protein interactions; altering the tract in POLG may result in suboptimal or improper mtDNA replication. To date over 150 disease mutations and 9 nonsynonymous polymorphisms in POLG have been found to be associated with autosomal recessive and dominant diseases.
Meta-analysis is a statistical method of large collection of analysis results from individual studies for the purpose of integrating the findings. Meta-analysis enable us to report that the effect is robust across the kinds of populations sampled, and also to estimate the magnitude of the effect more precisely than we could with any of the studies alone.
Several reports have implicated a association between the length of CAG-repeat in the polymerase y gene (pol y) and male infertility. However, such results have not been reproduced in other studies. In the present study, POLG-CAG repeat were analyzed in 535 healthy individuals from 6 Chinese Han populations living in different provinces. The frequencies of 10-CAG alleles and genotypes were 97.38% and 94.13%respectively; however, there was no significant difference among the 6 Chinese Han populations. We performed a pairwise comparison of different populations previously published on the frequency of the CAG-repeats genotype and found differences in the frequency of the three POLG CAG-repeats genotype between geographically-and ethnically-related populations. The prevalence of homozygous wild type (10/10) was shown to be exceedingly high in Chinese (97.38%). These results indicated that there is a significant difference in frequencies of the three CAG-repeat genotypes among different populations. Further, we determined the distribution of POLG-CAG repeat in 367 infertile men and 323 fertile men. Our study suggested that the distribution of POLG-CAG repeat alleles and genotypes were not significantly different between infertile (95.67%and 92.67%) and fertile men (97.22%and 94.44%). In a subsequent Meta-analysis combining our data with previous studies, a comparison of CAG-repeat alleles showed there was no obvious association with male infertility (pooled OR=0.94; 95%CI:0.60-1.48). The lack of significance appeared after combined genotypes with the following genetic models: homozygote comparison, heterozygote comparison, dominant model comparison, and recessive genetic comparison. In conclusion, the frequencies of POLG CAG-repeat variants are quite different in diverse ethnicities and this polymorphism may not be associated with Chinese male infertility. Based on a subsequent Meta-analysis, there was no obvious association between CAG-repeat variants of the POLG gene and male infertility.
引文
[1]Poongothai J, Gopenath T S. Manonayaki S. Genetics of human male infertility. Singapore Med. J.2009,50:336-347.
[2]阮健,杜卫东.男性不育与基因缺陷[J].遗传.2010(5)：411-422.
[3]Vogt P H. Molecular genetics of human male infertility:from genes to new therapeutic perspectives. Curr Pharm Des.2004,10(5):471-500.
[4]O'Flynn O B. Katherine L. Varghese A C, et al. The genetic causes of male factor infertility:A review. Fertility and sterility.2010,93(1):1-12.
[5]Maduro M R, Lamb D J. Understanding new genetics of male infertility. J Urol.2002,168(5): 2197-2205.
[6]Cram D S, O'Bryan M K, de Kretser D M. Male infertility geneties-the future. J Androl.2001, 22(5):738-746.
[7]St J J, Bowles E J, Amaral A. Sperm mitochondria and fertilisation. Soc Reprod Fertil Suppl. 2007,65:399-416.
[8]Hackstein J H, Hochstenbach R, Pearson P L. Towards an understanding of the genetics of human male infertility:lessons from flies. Trends Genet.2000,16(12):565-572.
[9]徐庆阳,彭弋峰.精子线粒体DNA与男性不育[J].中国男科学杂志.2004(5)：62-64.
[10]Rani D S, Carlus S J, Poongothai J, et al. CAG repeat variation in the mtDNA polymerase gamma is not associated with oligoasthenozoospermia. Int J Androl.2008.
[11]Amaral A, Ramalho-Santos J, St John J C. The expression of polymerase gamma and mitochondrial transcription factor A and the regulation of mitochondrial DNA content in mature human sperm. Human Reproduction.2007,22(6):1585.
[12]Chan S, Copeland W C. DNA polymerase gamma and mitochondrial disease:Understanding the consequence of POLG mutations. Biochimica et Biophysica Acta (BBA)-Bioenergetics.2009. 1787(5):312-319.
[13]Longley M J, Graziewicz M A, Bienstock R J, et al. Consequences of mutations in human DNA polymerase [gamma]. Gene.2005,354:125-131.
[14]Hudson G, Chinnery P F. Mitochondrial DNA polymerase-gamma and human disease. Hum Mol Genet.2006,15 Spec No 2:R244-R252.
[15]Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature.2004,429(6990):417-423.
[16]Spelbrink J N, Toivonen J M, Hakkaart G A, et al. In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem.2000, 275(32):24818-24828.
[17]刘舒媛,褚嘉祐POLG基因突变在人类疾病中作用的研究[J].国际遗传学杂志,2009,32(6)：441-444.
[18]Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online.2008,16(4):504-513.
[19]Rovio A T, Marchington D R, Donat S, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet.2001,29(3):261-262.
[20]Jensen M, Leffers H, Petersen J H, et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod.2004,19(1):65-70.
[21]Brusco A, Michielotto C. Gatta V. et al. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest.2006,29(1):1-4.
[22]Krausz C, Guarducci E, Becherini L, et al. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab.2004,89(9):4292-4297.
[23]Westerveld G H, Kaaij-Visser L, Tanck M, et al. CAG repeat length variation in the polymerase gamma (POLG) gene:effect on semen quality. Molecular human reproduction.2008, 14(4):245.
[24]Aknin-Seifer I E, Touraine R L, Lejeune H, et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod.2005,20(3):736-740.
[25]Organization. W H. Laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed.[M]. New York:Cambridge University Press,1999.
[26]张大嵩,钟文昭,张素,等Stata在Meta分析时异质性评价中的应用[J].循证医学.2008(4)：231-234.
[27]C J A. Meta-analysis in Stata TM.2001.
[28]Jp H. Measuring inconsistency in meta-analyses.2003:327,557-560.
[29]Higgins J P, Thompson S G. Quantifying heterogeneity in a meta-analysis. Stat Med.2002, 21(11):1539-1558.
[30]Egger M, Davey S G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ.1997,315(7109):629-634.
[31]Orwin R. A fail-safe N for effect size in meta-analysis. al of Educational Statistics Summer. 1983,8(Nov.2):157-159.
[32]Plaseski T, Noveski P, Dimitrovski C, et al. CAG Repeat Polymorphism of the Mitochondrial DNA Polymerase Gamma Gene in Macedonian Infertile and Fertile Men. Balkan Journal of Medical Genetics.2007,10(2):37-42.
[33]Harris T P, Gomas K P, Weir F, et al. Molecular analysis of polymerase gamma gene and mitochondrial polymorphism in fertile and subfertile men. Int J Androl.2006,29(3):421-433.
[34]Yao N, Zheng J F, Peng Y F, et al. [CAG repeats of DNA polymerase gamma in Chinese males and relationship of idiopathic male infertility to CAG repeats]. Zhonghua Nan Ke Xue. 2006,12(8):681-684,688.
[35]王洪源李宪Meta分析中失安全系数意义的探讨[J].中国卫生统计.2008,25(4).
[36]方积乾等麦劲壮李河meta分析中失安全系数的估计[J].循证医学.2006(5).
[37]Rozanska M, Sobczak K, Jasinska A, et al. CAG and CTG repeat polymorphism in exons of human genes shows distinct features at the expandable loci. Human Mutation.2007,28(5): 451-458.
[38]Kozlowski P, de Mezer M, Krzyzosiak W J. Trinucleotide repeats in human genome and exome. Nucleic Acids Res.2010,38(12):4027-4039.
[39]Subramanian S, Madgula V M, George R, et al. Triplet repeats in human genome: distribution and their association with genes and other genomic regions. Bioinformatics.2003, 19(5):549-552.
[40]Meloni R E A. A tetranucleotide polymorphic microsatellite, located in the first intron of the tyrosine hydroxylase Gene, acts as a transcription regulatory element in vitro. Hum. Mol. Genet. 1998,3:423-428.
[41]Gebhardt F E A. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J. Biol. Chem.,274:13176-13180.
[42]Wang Y H A G. Expanded CTG triplet blocks from Myotonic Dystrophy Gene create the strongest known natural nucleosome positioning elements. Genomics.1995,25.
[43]Nadir E E A. Microsatellite Spreading in the Human Genome:Evolutionary Mechanisms and Structural Implications. Proc. Natl. Acad. Sci.1996,93.
[44]Djian P. Evolution of simple repeats in DNA and their relation to human disease. Cell.1998, 94(2):155-160.
[45]Pearson C E, Nichol E K, Cleary J D. Repeat instability:mechanisms of dynamic mutations. Nat Rev Genet.2005,6(10):729-742.
[46]Goellner G M, Tester D, Thibodeau S, et al. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet.1997,60(4):879-890.
[47]陈竺,李伟俞,曼熊慧,等.人类基因组计划的机遇和挑战：Ⅰ.从结构基因组学到功能基因组学[J].生命的化学.1998(5)：7-15.
[48]Hummerich H, Lehrach H. Trinucleotide repeat expansion and human disease. Electrophoresis.1995,16(9):1698-1704.
[49]Ashley C J, Warren S T. Trinucleotide repeat expansion and human disease. Annu Rev Genet. 1995,29:703-728.
[50]Ferlin A, Bartoloni L, Rizzo G, et al. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod.2004,10(6):417-421.
[51]蔡善荣,刘希永,郑树,等.人类基因组STR及其应用[J].国外医学.遗传学分册.2000(2)：60-63.
[52]Bennett S T, Lucassen A M, Gough S C, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995,9(3):284-292.
[53]Chen W M, Liu Y F, Lin M W, et al. Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12ql3. Am J Hum Genet.2004,75(2): 310-317.
[54]张俊华,商洪才,张伯礼.系统评价和neta分析质量的评价方法[J].中西医结合学报.2008(4)：337-340.
[55]但汉雷,白杨,张亚历,等Meta分析方法及其医学科研价值与评价[J].中华医学科研管理杂志.2003(1)：13-16.
[56]Weekley J S. Smith B J, Pradhan M. The intersection of health informatics and evidence-based medicine:computer-based systems to assist clinicians. Med J Aust.2000,173(7): 376-378.
[57]朱立勤,白玫,李敬永,等.Meta分析及其在药物治疗质量评价中的应用[J].中国新药杂志.2007(24)：1997-2000.
[58]钟文昭,吴一龙,谷力加.Review Manager(RevMan)——临床医生通向Meta分析的桥梁[J].循证医学.2003(4)：234-246.
[59]Richardson W S, Wilson M C, Williams J J, et al. Users'guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group. JAMA.2000,284(7):869-875.
[60]柏建岭,钟文昭,郑明华,等.Stata在Meta分析中的应用[J].循证医学.2007(6)：363-368.
[61]汪求真,周晓彬,滕洪松.中国人群饮食因素与食管癌Meta分析[J].中国肿瘤.2007(1)：3-7.
[62]Ruiz-Pesini E, Mishmar D, Brandon M, et al. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science.2004.303(5655):223-226.
[63]Mishmar D. Ruiz-Pesini E, Golik P, et al. Natural selection shaped regional mtDNA variation in humans. Proc Natl Acad Sci USA.2003,100(1):171-176.
[64]Pinar E. Coskun E R A D. Control region mtDNA variants:Longevity, climatic adaptation, and a forensic conundrum. PNAS.,100(5):2174-2176.
[65]Anja Rovio V T A L. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. European Journal Of Human Genetics.1999,7.
[66]Malyarchuk B A, Papuga M, Grzybowski T, et al. Low variability of the POLG (CAG) n repeat in north Eurasian populations. Human Biology.2005,77(3):355-366.
[67]Sobczak K, Krzyzosiak W J. Patterns of CAG repeat interruptions in SCA1 and SCA2 genes in relation to repeat instability. Hum Mutat.2004,24(3):236-247.
[68]Butland S L, Devon R S, Huang Y, et al. CAG-encoded polyglutamine length polymorphism in the human genome. BMC Genomics.2007,8:126.
[69]Rolfsmeier M L, Lahue R S. Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae. Mol Cell Biol.2000,20(1):173-180.
[70]Williams A J, Paulson H L. Polyglutamine neurodegeneration:protein misfolding revisited. Trends "Neurosci.2008,31(10):521-528.
[71]Anvret A, Westerlund M, Sydow O, et al. Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG 1) is associated with Parkinson's disease in Sweden. Neurosci Lett. 2010,485(2):117-120.
[72]Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature.2004,429(6990):417-423.
[73]Tuttelmann F, Rajpert-De Meyts E, Nieschlag E, et al. Gene polymorphisms and male infertility a meta-analysis and literature review. Reproductive biomedicine online.2007,15(6): 643-658.
[1]Saxena R, de Vries JW, Repping S, Alagappan RK, Skaletsky H, Brown LG, Ma P, Chen E, Hoovers JM, Page DC. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics.2000 Aug 1;67(3):256-67.
[2]Ferlin A, Moro E, Onisto M, Toscano E, Bettella A, Foresta C. Absence of testicular DAZ gene expression in idiopathic severe testiculopathies. Hum Reprod.1999 Sep;14(9):2286-9
[3]Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D. Hovatta O, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet.1995 Aug;10(4):383-93.
[4]Eberhart CG, Maines JZ, Wasserman SA. Meiotic cell cycle requirement for a fly homologue of human Deleted in Azoospermia. Nature.1996 Jun 27;381(6585):783-5.
[5]Reijo R, Alagappan RK. Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoosperrnia factor gene on Y chromosome. Lancet.1996 May 11;347(9011):1290-3.
[6]Nakahori Y, Kuroki Y, Komaki R, Kondoh N, Namiki M, Iwamoto T, Toda T, Kobayashi K. The Y chromosome region essential for spermatogenesis. Horm Res.1996;46 Suppl 1:20-3.
[7]Najmabadi H, Huang V. Yen P, Subbarao MN, Bhasin D. Banaag L, Naseeruddin S, de Kretser DM, Baker HW, McLachlan RI, et al. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab.1996 Apr;81(4):1347-52.
[8]Yang Y et al中国男性不育的重要遗传病因：染色体异常与Y染色体AZFc区DAZ基因拷贝缺火Zhonghua Nan Ke Xue,2005 Jul.l 1(7):494-8
[9]Martinez MC, Bernabe MJ, Gomez E, Ballesteros A, Landeras J, Glover G, Gil-Salom M, Remohi J, Pellicer A. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients. J Androl.2000 Sep-Oct;21(5):651-5.
[10]Ma K et al. A Y chromosome gene family with RNA-binding protein homology:candidates for the azoospennia factor AZF controlling human spermatogenesis.Cell,1993,75:1287-1295.
[11]冀荣俊,刘刚.男性特发性不育症与RBM基因关系的探讨[J].中国性科学,2004,(05)
[12]Mahadevaiah SK, Odorisio T, Elliott DJ, Rattigan A, Szot M. Laval SH, Washbum LL, McCarrey JR, Cattanach BM, Lovell-Badge R, Burgoyne PS. Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spennatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum Mol Genet.1998 Apr;7(4):715-27.
[13]Kao S, Chao HT, Wei YH.Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm.Biol Reprod.1995 Apr;52(4):729-36.
[14]St John JC, Jokhi RP, Barratt CL.The impact of mitochondrial genetics on male infertility.Int J Androl.2005 Apr;28(2):65-73. Review.
[15]Kao SH, Chao HT, Wei YH.Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod.1998 Jul;4(7):657-66.
[16]Kao SH, Chao HT, Liu HW, Liao TL, Wei YH. Sperm mitochondrial DNA depletion in men with asthenospermia.Fertil Steril.2004 Jul;82(1):66-73.
[17]Cummins JM, Jequier AM, Martin R, Mehmet D, Goldblatt J. Semen levels of mitochondrial DNA deletions in men attending an infertility clinic do not correlate with phenotype.Int J Androl. 1998Feb;21(1):47-52.
[18]Ruiz-Pesini E, Lapena AC, Diez-Sanchez C. Perez-Martos A, Montoya J, Alvarez E, Diaz M, Urries A, Montoro L, Lopez-Perez MJ, Enriquez JA. Human mtDNA haplogroups associated with high or reduced spermatozoa motility.Am J Hum Genet.2000 Sep;67(3):682-96. Epub 2000 Aug 9.
[19]May-Panlop P, Chre Atien MF, Savagner F, et al. Hum Reprod 2003; 18(3):550-6
[20]Ropp PA, Copeland WC.Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma.Genomics.1996 Sep 15;36(3):449-58.
[21]Rovio AT, Abel J, Ahola AL, Andres AM, Bertranpetit J, Blancher A, Bontrop RE, Chemnick LG, Cooke HJ, Cummins JM, Davis HA, Elliott DJ, Fritsche E, Hargreave TB, Hoffman SM, Jequier AM, Kao SH, Kim HS, Marchington DR, Mehmet D, Otting N, Poulton J, Ryder OA, Schuppe HC, Takenaka O, Wei YH, Wichmann L, Jacobs HT. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mamm Genome.2004 Jun;15(6):492-502.
[22]Rovio AT, Marchington DR, Donat S, Schuppe HC, Abel J, Fritsche E, Elliott DJ, Laippala P, Ahola AL, McNay D, Harrison RF, Hughes B. Barrett T, Bailey DM, Mehmet D, Jequier AM, Hargreave TB. Kao SH, Cummins JM, Barton DE, Cooke HJ, Wei YH, Wichmann L, Poulton J, Jacobs HT. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet.2001 Nov;29(3):261-2.
[23]Jensen M, Leffers H, Petersen JH, Nyboe Andersen A. Jorgensen N, Carlsen E, Jensen TK, Skakkebaek NE, Rajpert-De Meyts E. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod.2004 Jan;19(1):65-70.
[24]Westerveld GH, Kaaij-Visser L, Tanck M, van der Veen F, Repping S. CAG repeat length variation in the polymerase gamma (POLG) gene:effect on semen quality. Mol Hum Reprod. 2008 Apr;14(4):245-9. Epub 2008 Mar 3.
[25]Brusco A, Michielotto C, Gatta V, Foresta C, Matullo G, Zeviani M, Ferrari G, Dragone E, Calabrese G, Rossato M. Stuppia L, Migone N. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest.2006 Jan;29(1):1-4.
[26]Krausz C, Guarducci E, Becherini L, Degl'Innocenti S, Gerace L, Balercia G, Forti G. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab. 2004 Sep;89(9):4292-7.
[27]Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM. Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT.In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells.J Biol Chem.2000 Aug 11;275(32):24818-28.
[28]Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann Neurol.1999 Jan;45(1):54-8.
[29]Rovio A, Tiranti V, Bednarz AL, Suomalainen A, Spelbrink JN, Lecrenier N, Melberg A, Zeviani M, Poulton J. Foury F, Jacobs HT. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. Eur J Hum Genet.1999 Feb-Mar;7(2):140-6.
[30]Aknin-Seifer IE. Touraine RL, Lejeune H, Jimenez C. Chouteau J, Siffroi JP, McElreavey K, Bienvenu T, Patrat C. Levy R. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod.2005 Mar;20(3):736-40. Epub 2005 Jan 13.
[31]Malyarchuk BA. Papuga M, Grzybowski T, Rogozin IB, Wozniak M, Derenko MV. Rychkov SY. Czarny J, Zakharov IA, Miscicka-Sliwka D. Low variability of the POLG (CAG)n repeat in north Eurasian populations. Hum Biol.2005 Jun;77(3):355-65.
[32]Gottlieb B, Lombroso R, Beitel LK, et al. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online.2005,10(1):42-48
[33]Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C. Male infertility and androgen receptor gene mutations:clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf).2006 Nov;65(5):606-10.
[34]Watkins WS et al.Population genetics of trinucleotide repeat polymorphism. Hum Mol Genet, 1995.4(9):1485-1491.
[35]Ferlin A, Bartoloni L, Rizzo G, Roverato A, Garolla A, Foresta C. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod.2004 Jun; 10(6):417-21. Epub 2004 Mar 25.
[36]卢少明,陈子江,赵力新,李媛,高选.无精或严重少弱精症患者雄激素受体基因(CAG)n多态性的研究.中华泌尿外科杂志,2005 Nov；26(11)：745.
[37]Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends Endocrinol Metab.2005 Oct;16(8):368-73.
[38]Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D, Nieschlag E. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab.1999 Feb;84(2):751-5.
[39]Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Ando S. Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa:evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. J Clin Endocrinol Metab.2004 Mar;89(3):1443-51.
[40]Kukuvitis A, Georgiou I, Bouba I, Tsirka A, Giannouli CH, Yapijakis C, Tarlatzis B, Bontis J, Lolis D, Sofikitis N, Papadimas J. Association of oestrogen receptor alpha polymorphisms and androgen receptor CAG trinucleotide repeats with male infertility:a study in 109 Greek infertile men. Int J Androl.2002 Jun;25(3):149-52.
[41]Galan JJ, Buch B, Cruz N, Segura A, Moron FJ, Bassas L, Martinez-Pineiro L, Real LM, Ruiz A. Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology. Fertil Steril.2005 Oct;84(4):910-8.
[42]Suzuki Y, Sasagawa I, Itoh K, Ashida J, Muroya K, Ogata T. Estrogen receptor alpha gene polymorphism is associated with idiopathic azoospermia. Fertil Steril.2002 Dec;78(6):1341-3.
[43]Guarducci E, Nuti F, Becherini L, Rotondi M, Balercia G, Forti G, Krausz C. Estrogen receptor alpha promoter polymorphism:stronger estrogen action is coupled with lower sperm count. Hum Reprod.2006 Apr;21(4):994-1001. Epub 2006 Jan 5.
[44]Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet,1998;62:1258-60.
[45]Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med 2001; 344:1172-3.
[46]Singh K, Singh SK, Sah R, Singh I, Raman R. Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Int J Androl 2005; 28:115-9.
[47]Park JH, Lee HC, Jeong YM, et al. MTHFR C677T polymorphism associates with unexplained infertility male factors. J Assist Reprod Genet 2005;22:361-8.
[48]Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril 2003; 80:1190-1.
[49]Stuppia L, Gatta V, Scarciolla O, Colosimo A, Guanciali-Franchi P, Calabrese G et al. The methylenetetrahydrofolate reductase MTHFR C677T polymorphism and male infertility in Italy. J Endocrinol Invest 2003; 26:620-2.
[50]Paracchini V, Garte S, Taioli E. MTHFR C677T polymorphism, GSTM1 deletion and male infertility:a possible suggestion of a gene-gene interaction? Biomarkers 2006; 11:53-60.
[51]Foresta C, Garolla A, Bartoloni L, Bettella A, Ferlin A. Genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. J Clin Endocrinol Metab.2005 Jan;90(1):152-6. Epub 2004 Oct 27.
[52]Schulz S, Jakubiczka S, Kropf S, Nickel I, Muschke P, Kleinstein J. Increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males. Fertil Steril. 2006Jan;85(1):135-8.
[53]Jiang MC, Lien YR, Chen SU, Ko TM, Ho HN, Yang YS. Transmission of de novo mutations of the deleted in azoospermia genes from a severely oligozoospermic male to a son via intracytoplasmic sperm injection. Fertil Steril.1999 Jun;71(6):1029-32.
[54]Mulhall JP, Reijo R, Alagappan R, Brown L, Page D, Carson R, Oates RD. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod.1997 Mar;12(3):503-8.
[55]Foresta C, Moro E, Ferlin A. Prognostic value of Y deletion analysis. The role of current methods. Hum Reprod.2001 Aug; 16(8):1543-7.
[1]Trifunovic A, Wredenberg A, Falkenberg M, et al Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature,2004,429:417-23.
[2]Spelbrink JN, Toivonen JM, Hakkaart GA, et al In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem, 2000,275:24818-28.
[3]Longley MJ, Ropp PA, Lim SE, el al Characterization of the native and recombinant catalytic subunit of human DNA polymerase gamma:identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity. Biochemistry.1998,37:10529-39.
[4]Kunkel TA, Soni A. Exonucleolytic proofreading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma. J Biol Chem,1988,263:4450-9.
[5]Graziewicz MA, Longley MJ, Bienstock RJ, et al Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol,2004,11:770-6.
[6]Ponamarev MV, Longley MJ, Nguyen D, et al Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis. J Biol Chem,2002,277:15225-8.
[7]Mancuso M, Filosto M, Oh SJ, et al A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol,2004,61:1777-9.
[8]Naviaux RK, Nguyen KV. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol,2005,58:491.
[9]Naviaux RK, Nyhan WL, Barshop BA, et al. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann Neurol,1999,45:54-8.
[10]Naviaux RK, Nguyen KV. POLG mutations associated with Alpers'syndrome and mitochondrial DNA depletion. Ann Neurol,2004,55:706-12.
[11]Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics,1996,36:449-58.
[12]Rovio AT, Abel J, Ahola AL, el al. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mamm Genome,2004,15:492-502.
[13]Rovio AT, Marchington DR, Donat S, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet,2001,29:261-2.
[14]Jensen M, Leffers H, Petersen JH, et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod,2004,19:65-70.
[15]Brusco A, Michielotto C, Gatta V, et al. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest,2006,29:1-4.
[16]Krausz C, Guarducci E, Becherini L, et al. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab,2004,89:4292-7.
[17]Aknin-Seifer IE, Touraine RL, Lejeune H, et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod,2005,20:736-40.
[18]Rani DS, Carlus SJ, Poongothai J, et al. CAG repeat variation in the mtDNA polymerase gamma is not associated with oligoasthenozoospermia. Int J Androl,2008.
[19]Rovio A, Tiranti V, Bednarz AL, et al. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. Eur J Hum Genet,1999,7:140-6.
[20]Malyarchuk BA, Papuga M, Grzybowski T, et al. Low variability of the POLG (CAG)n repeat in north Eurasian populations. Hum Biol,2005,77:355-65.
[21]Schapira AH. Mitochondrial disease. Lancet,2006,368:70-82.
[2]阮健,杜卫东.男性不育与基因缺陷[J].遗传.2010(5)：411-422.
[3]Vogt P H. Molecular genetics of human male infertility:from genes to new therapeutic perspectives. Curr Pharm Des.2004,10(5):471-500.
[4]O'Flynn O B. Katherine L. Varghese A C, et al. The genetic causes of male factor infertility:A review. Fertility and sterility.2010,93(1):1-12.
[5]Maduro M R, Lamb D J. Understanding new genetics of male infertility. J Urol.2002,168(5): 2197-2205.
[6]Cram D S, O'Bryan M K, de Kretser D M. Male infertility geneties-the future. J Androl.2001, 22(5):738-746.
[7]St J J, Bowles E J, Amaral A. Sperm mitochondria and fertilisation. Soc Reprod Fertil Suppl. 2007,65:399-416.
[8]Hackstein J H, Hochstenbach R, Pearson P L. Towards an understanding of the genetics of human male infertility:lessons from flies. Trends Genet.2000,16(12):565-572.
[9]徐庆阳,彭弋峰.精子线粒体DNA与男性不育[J].中国男科学杂志.2004(5)：62-64.
[10]Rani D S, Carlus S J, Poongothai J, et al. CAG repeat variation in the mtDNA polymerase gamma is not associated with oligoasthenozoospermia. Int J Androl.2008.
[11]Amaral A, Ramalho-Santos J, St John J C. The expression of polymerase gamma and mitochondrial transcription factor A and the regulation of mitochondrial DNA content in mature human sperm. Human Reproduction.2007,22(6):1585.
[12]Chan S, Copeland W C. DNA polymerase gamma and mitochondrial disease:Understanding the consequence of POLG mutations. Biochimica et Biophysica Acta (BBA)-Bioenergetics.2009. 1787(5):312-319.
[13]Longley M J, Graziewicz M A, Bienstock R J, et al. Consequences of mutations in human DNA polymerase [gamma]. Gene.2005,354:125-131.
[14]Hudson G, Chinnery P F. Mitochondrial DNA polymerase-gamma and human disease. Hum Mol Genet.2006,15 Spec No 2:R244-R252.
[15]Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature.2004,429(6990):417-423.
[16]Spelbrink J N, Toivonen J M, Hakkaart G A, et al. In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem.2000, 275(32):24818-24828.
[17]刘舒媛,褚嘉祐POLG基因突变在人类疾病中作用的研究[J].国际遗传学杂志,2009,32(6)：441-444.
[18]Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online.2008,16(4):504-513.
[19]Rovio A T, Marchington D R, Donat S, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet.2001,29(3):261-262.
[20]Jensen M, Leffers H, Petersen J H, et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod.2004,19(1):65-70.
[21]Brusco A, Michielotto C. Gatta V. et al. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest.2006,29(1):1-4.
[22]Krausz C, Guarducci E, Becherini L, et al. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab.2004,89(9):4292-4297.
[23]Westerveld G H, Kaaij-Visser L, Tanck M, et al. CAG repeat length variation in the polymerase gamma (POLG) gene:effect on semen quality. Molecular human reproduction.2008, 14(4):245.
[24]Aknin-Seifer I E, Touraine R L, Lejeune H, et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod.2005,20(3):736-740.
[25]Organization. W H. Laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed.[M]. New York:Cambridge University Press,1999.
[26]张大嵩,钟文昭,张素,等Stata在Meta分析时异质性评价中的应用[J].循证医学.2008(4)：231-234.
[27]C J A. Meta-analysis in Stata TM.2001.
[28]Jp H. Measuring inconsistency in meta-analyses.2003:327,557-560.
[29]Higgins J P, Thompson S G. Quantifying heterogeneity in a meta-analysis. Stat Med.2002, 21(11):1539-1558.
[30]Egger M, Davey S G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ.1997,315(7109):629-634.
[31]Orwin R. A fail-safe N for effect size in meta-analysis. al of Educational Statistics Summer. 1983,8(Nov.2):157-159.
[32]Plaseski T, Noveski P, Dimitrovski C, et al. CAG Repeat Polymorphism of the Mitochondrial DNA Polymerase Gamma Gene in Macedonian Infertile and Fertile Men. Balkan Journal of Medical Genetics.2007,10(2):37-42.
[33]Harris T P, Gomas K P, Weir F, et al. Molecular analysis of polymerase gamma gene and mitochondrial polymorphism in fertile and subfertile men. Int J Androl.2006,29(3):421-433.
[34]Yao N, Zheng J F, Peng Y F, et al. [CAG repeats of DNA polymerase gamma in Chinese males and relationship of idiopathic male infertility to CAG repeats]. Zhonghua Nan Ke Xue. 2006,12(8):681-684,688.
[35]王洪源李宪Meta分析中失安全系数意义的探讨[J].中国卫生统计.2008,25(4).
[36]方积乾等麦劲壮李河meta分析中失安全系数的估计[J].循证医学.2006(5).
[37]Rozanska M, Sobczak K, Jasinska A, et al. CAG and CTG repeat polymorphism in exons of human genes shows distinct features at the expandable loci. Human Mutation.2007,28(5): 451-458.
[38]Kozlowski P, de Mezer M, Krzyzosiak W J. Trinucleotide repeats in human genome and exome. Nucleic Acids Res.2010,38(12):4027-4039.
[39]Subramanian S, Madgula V M, George R, et al. Triplet repeats in human genome: distribution and their association with genes and other genomic regions. Bioinformatics.2003, 19(5):549-552.
[40]Meloni R E A. A tetranucleotide polymorphic microsatellite, located in the first intron of the tyrosine hydroxylase Gene, acts as a transcription regulatory element in vitro. Hum. Mol. Genet. 1998,3:423-428.
[41]Gebhardt F E A. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J. Biol. Chem.,274:13176-13180.
[42]Wang Y H A G. Expanded CTG triplet blocks from Myotonic Dystrophy Gene create the strongest known natural nucleosome positioning elements. Genomics.1995,25.
[43]Nadir E E A. Microsatellite Spreading in the Human Genome:Evolutionary Mechanisms and Structural Implications. Proc. Natl. Acad. Sci.1996,93.
[44]Djian P. Evolution of simple repeats in DNA and their relation to human disease. Cell.1998, 94(2):155-160.
[45]Pearson C E, Nichol E K, Cleary J D. Repeat instability:mechanisms of dynamic mutations. Nat Rev Genet.2005,6(10):729-742.
[46]Goellner G M, Tester D, Thibodeau S, et al. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet.1997,60(4):879-890.
[47]陈竺,李伟俞,曼熊慧,等.人类基因组计划的机遇和挑战：Ⅰ.从结构基因组学到功能基因组学[J].生命的化学.1998(5)：7-15.
[48]Hummerich H, Lehrach H. Trinucleotide repeat expansion and human disease. Electrophoresis.1995,16(9):1698-1704.
[49]Ashley C J, Warren S T. Trinucleotide repeat expansion and human disease. Annu Rev Genet. 1995,29:703-728.
[50]Ferlin A, Bartoloni L, Rizzo G, et al. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod.2004,10(6):417-421.
[51]蔡善荣,刘希永,郑树,等.人类基因组STR及其应用[J].国外医学.遗传学分册.2000(2)：60-63.
[52]Bennett S T, Lucassen A M, Gough S C, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995,9(3):284-292.
[53]Chen W M, Liu Y F, Lin M W, et al. Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12ql3. Am J Hum Genet.2004,75(2): 310-317.
[54]张俊华,商洪才,张伯礼.系统评价和neta分析质量的评价方法[J].中西医结合学报.2008(4)：337-340.
[55]但汉雷,白杨,张亚历,等Meta分析方法及其医学科研价值与评价[J].中华医学科研管理杂志.2003(1)：13-16.
[56]Weekley J S. Smith B J, Pradhan M. The intersection of health informatics and evidence-based medicine:computer-based systems to assist clinicians. Med J Aust.2000,173(7): 376-378.
[57]朱立勤,白玫,李敬永,等.Meta分析及其在药物治疗质量评价中的应用[J].中国新药杂志.2007(24)：1997-2000.
[58]钟文昭,吴一龙,谷力加.Review Manager(RevMan)——临床医生通向Meta分析的桥梁[J].循证医学.2003(4)：234-246.
[59]Richardson W S, Wilson M C, Williams J J, et al. Users'guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group. JAMA.2000,284(7):869-875.
[60]柏建岭,钟文昭,郑明华,等.Stata在Meta分析中的应用[J].循证医学.2007(6)：363-368.
[61]汪求真,周晓彬,滕洪松.中国人群饮食因素与食管癌Meta分析[J].中国肿瘤.2007(1)：3-7.
[62]Ruiz-Pesini E, Mishmar D, Brandon M, et al. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science.2004.303(5655):223-226.
[63]Mishmar D. Ruiz-Pesini E, Golik P, et al. Natural selection shaped regional mtDNA variation in humans. Proc Natl Acad Sci USA.2003,100(1):171-176.
[64]Pinar E. Coskun E R A D. Control region mtDNA variants:Longevity, climatic adaptation, and a forensic conundrum. PNAS.,100(5):2174-2176.
[65]Anja Rovio V T A L. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. European Journal Of Human Genetics.1999,7.
[66]Malyarchuk B A, Papuga M, Grzybowski T, et al. Low variability of the POLG (CAG) n repeat in north Eurasian populations. Human Biology.2005,77(3):355-366.
[67]Sobczak K, Krzyzosiak W J. Patterns of CAG repeat interruptions in SCA1 and SCA2 genes in relation to repeat instability. Hum Mutat.2004,24(3):236-247.
[68]Butland S L, Devon R S, Huang Y, et al. CAG-encoded polyglutamine length polymorphism in the human genome. BMC Genomics.2007,8:126.
[69]Rolfsmeier M L, Lahue R S. Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae. Mol Cell Biol.2000,20(1):173-180.
[70]Williams A J, Paulson H L. Polyglutamine neurodegeneration:protein misfolding revisited. Trends "Neurosci.2008,31(10):521-528.
[71]Anvret A, Westerlund M, Sydow O, et al. Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG 1) is associated with Parkinson's disease in Sweden. Neurosci Lett. 2010,485(2):117-120.
[72]Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature.2004,429(6990):417-423.
[73]Tuttelmann F, Rajpert-De Meyts E, Nieschlag E, et al. Gene polymorphisms and male infertility a meta-analysis and literature review. Reproductive biomedicine online.2007,15(6): 643-658.
[1]Saxena R, de Vries JW, Repping S, Alagappan RK, Skaletsky H, Brown LG, Ma P, Chen E, Hoovers JM, Page DC. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics.2000 Aug 1;67(3):256-67.
[2]Ferlin A, Moro E, Onisto M, Toscano E, Bettella A, Foresta C. Absence of testicular DAZ gene expression in idiopathic severe testiculopathies. Hum Reprod.1999 Sep;14(9):2286-9
[3]Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D. Hovatta O, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet.1995 Aug;10(4):383-93.
[4]Eberhart CG, Maines JZ, Wasserman SA. Meiotic cell cycle requirement for a fly homologue of human Deleted in Azoospermia. Nature.1996 Jun 27;381(6585):783-5.
[5]Reijo R, Alagappan RK. Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoosperrnia factor gene on Y chromosome. Lancet.1996 May 11;347(9011):1290-3.
[6]Nakahori Y, Kuroki Y, Komaki R, Kondoh N, Namiki M, Iwamoto T, Toda T, Kobayashi K. The Y chromosome region essential for spermatogenesis. Horm Res.1996;46 Suppl 1:20-3.
[7]Najmabadi H, Huang V. Yen P, Subbarao MN, Bhasin D. Banaag L, Naseeruddin S, de Kretser DM, Baker HW, McLachlan RI, et al. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab.1996 Apr;81(4):1347-52.
[8]Yang Y et al中国男性不育的重要遗传病因：染色体异常与Y染色体AZFc区DAZ基因拷贝缺火Zhonghua Nan Ke Xue,2005 Jul.l 1(7):494-8
[9]Martinez MC, Bernabe MJ, Gomez E, Ballesteros A, Landeras J, Glover G, Gil-Salom M, Remohi J, Pellicer A. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients. J Androl.2000 Sep-Oct;21(5):651-5.
[10]Ma K et al. A Y chromosome gene family with RNA-binding protein homology:candidates for the azoospennia factor AZF controlling human spermatogenesis.Cell,1993,75:1287-1295.
[11]冀荣俊,刘刚.男性特发性不育症与RBM基因关系的探讨[J].中国性科学,2004,(05)
[12]Mahadevaiah SK, Odorisio T, Elliott DJ, Rattigan A, Szot M. Laval SH, Washbum LL, McCarrey JR, Cattanach BM, Lovell-Badge R, Burgoyne PS. Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spennatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum Mol Genet.1998 Apr;7(4):715-27.
[13]Kao S, Chao HT, Wei YH.Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm.Biol Reprod.1995 Apr;52(4):729-36.
[14]St John JC, Jokhi RP, Barratt CL.The impact of mitochondrial genetics on male infertility.Int J Androl.2005 Apr;28(2):65-73. Review.
[15]Kao SH, Chao HT, Wei YH.Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod.1998 Jul;4(7):657-66.
[16]Kao SH, Chao HT, Liu HW, Liao TL, Wei YH. Sperm mitochondrial DNA depletion in men with asthenospermia.Fertil Steril.2004 Jul;82(1):66-73.
[17]Cummins JM, Jequier AM, Martin R, Mehmet D, Goldblatt J. Semen levels of mitochondrial DNA deletions in men attending an infertility clinic do not correlate with phenotype.Int J Androl. 1998Feb;21(1):47-52.
[18]Ruiz-Pesini E, Lapena AC, Diez-Sanchez C. Perez-Martos A, Montoya J, Alvarez E, Diaz M, Urries A, Montoro L, Lopez-Perez MJ, Enriquez JA. Human mtDNA haplogroups associated with high or reduced spermatozoa motility.Am J Hum Genet.2000 Sep;67(3):682-96. Epub 2000 Aug 9.
[19]May-Panlop P, Chre Atien MF, Savagner F, et al. Hum Reprod 2003; 18(3):550-6
[20]Ropp PA, Copeland WC.Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma.Genomics.1996 Sep 15;36(3):449-58.
[21]Rovio AT, Abel J, Ahola AL, Andres AM, Bertranpetit J, Blancher A, Bontrop RE, Chemnick LG, Cooke HJ, Cummins JM, Davis HA, Elliott DJ, Fritsche E, Hargreave TB, Hoffman SM, Jequier AM, Kao SH, Kim HS, Marchington DR, Mehmet D, Otting N, Poulton J, Ryder OA, Schuppe HC, Takenaka O, Wei YH, Wichmann L, Jacobs HT. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mamm Genome.2004 Jun;15(6):492-502.
[22]Rovio AT, Marchington DR, Donat S, Schuppe HC, Abel J, Fritsche E, Elliott DJ, Laippala P, Ahola AL, McNay D, Harrison RF, Hughes B. Barrett T, Bailey DM, Mehmet D, Jequier AM, Hargreave TB. Kao SH, Cummins JM, Barton DE, Cooke HJ, Wei YH, Wichmann L, Poulton J, Jacobs HT. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet.2001 Nov;29(3):261-2.
[23]Jensen M, Leffers H, Petersen JH, Nyboe Andersen A. Jorgensen N, Carlsen E, Jensen TK, Skakkebaek NE, Rajpert-De Meyts E. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod.2004 Jan;19(1):65-70.
[24]Westerveld GH, Kaaij-Visser L, Tanck M, van der Veen F, Repping S. CAG repeat length variation in the polymerase gamma (POLG) gene:effect on semen quality. Mol Hum Reprod. 2008 Apr;14(4):245-9. Epub 2008 Mar 3.
[25]Brusco A, Michielotto C, Gatta V, Foresta C, Matullo G, Zeviani M, Ferrari G, Dragone E, Calabrese G, Rossato M. Stuppia L, Migone N. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest.2006 Jan;29(1):1-4.
[26]Krausz C, Guarducci E, Becherini L, Degl'Innocenti S, Gerace L, Balercia G, Forti G. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab. 2004 Sep;89(9):4292-7.
[27]Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM. Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT.In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells.J Biol Chem.2000 Aug 11;275(32):24818-28.
[28]Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann Neurol.1999 Jan;45(1):54-8.
[29]Rovio A, Tiranti V, Bednarz AL, Suomalainen A, Spelbrink JN, Lecrenier N, Melberg A, Zeviani M, Poulton J. Foury F, Jacobs HT. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. Eur J Hum Genet.1999 Feb-Mar;7(2):140-6.
[30]Aknin-Seifer IE. Touraine RL, Lejeune H, Jimenez C. Chouteau J, Siffroi JP, McElreavey K, Bienvenu T, Patrat C. Levy R. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod.2005 Mar;20(3):736-40. Epub 2005 Jan 13.
[31]Malyarchuk BA. Papuga M, Grzybowski T, Rogozin IB, Wozniak M, Derenko MV. Rychkov SY. Czarny J, Zakharov IA, Miscicka-Sliwka D. Low variability of the POLG (CAG)n repeat in north Eurasian populations. Hum Biol.2005 Jun;77(3):355-65.
[32]Gottlieb B, Lombroso R, Beitel LK, et al. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online.2005,10(1):42-48
[33]Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C. Male infertility and androgen receptor gene mutations:clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf).2006 Nov;65(5):606-10.
[34]Watkins WS et al.Population genetics of trinucleotide repeat polymorphism. Hum Mol Genet, 1995.4(9):1485-1491.
[35]Ferlin A, Bartoloni L, Rizzo G, Roverato A, Garolla A, Foresta C. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod.2004 Jun; 10(6):417-21. Epub 2004 Mar 25.
[36]卢少明,陈子江,赵力新,李媛,高选.无精或严重少弱精症患者雄激素受体基因(CAG)n多态性的研究.中华泌尿外科杂志,2005 Nov；26(11)：745.
[37]Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends Endocrinol Metab.2005 Oct;16(8):368-73.
[38]Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D, Nieschlag E. Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab.1999 Feb;84(2):751-5.
[39]Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Ando S. Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa:evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. J Clin Endocrinol Metab.2004 Mar;89(3):1443-51.
[40]Kukuvitis A, Georgiou I, Bouba I, Tsirka A, Giannouli CH, Yapijakis C, Tarlatzis B, Bontis J, Lolis D, Sofikitis N, Papadimas J. Association of oestrogen receptor alpha polymorphisms and androgen receptor CAG trinucleotide repeats with male infertility:a study in 109 Greek infertile men. Int J Androl.2002 Jun;25(3):149-52.
[41]Galan JJ, Buch B, Cruz N, Segura A, Moron FJ, Bassas L, Martinez-Pineiro L, Real LM, Ruiz A. Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology. Fertil Steril.2005 Oct;84(4):910-8.
[42]Suzuki Y, Sasagawa I, Itoh K, Ashida J, Muroya K, Ogata T. Estrogen receptor alpha gene polymorphism is associated with idiopathic azoospermia. Fertil Steril.2002 Dec;78(6):1341-3.
[43]Guarducci E, Nuti F, Becherini L, Rotondi M, Balercia G, Forti G, Krausz C. Estrogen receptor alpha promoter polymorphism:stronger estrogen action is coupled with lower sperm count. Hum Reprod.2006 Apr;21(4):994-1001. Epub 2006 Jan 5.
[44]Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet,1998;62:1258-60.
[45]Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med 2001; 344:1172-3.
[46]Singh K, Singh SK, Sah R, Singh I, Raman R. Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Int J Androl 2005; 28:115-9.
[47]Park JH, Lee HC, Jeong YM, et al. MTHFR C677T polymorphism associates with unexplained infertility male factors. J Assist Reprod Genet 2005;22:361-8.
[48]Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril 2003; 80:1190-1.
[49]Stuppia L, Gatta V, Scarciolla O, Colosimo A, Guanciali-Franchi P, Calabrese G et al. The methylenetetrahydrofolate reductase MTHFR C677T polymorphism and male infertility in Italy. J Endocrinol Invest 2003; 26:620-2.
[50]Paracchini V, Garte S, Taioli E. MTHFR C677T polymorphism, GSTM1 deletion and male infertility:a possible suggestion of a gene-gene interaction? Biomarkers 2006; 11:53-60.
[51]Foresta C, Garolla A, Bartoloni L, Bettella A, Ferlin A. Genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. J Clin Endocrinol Metab.2005 Jan;90(1):152-6. Epub 2004 Oct 27.
[52]Schulz S, Jakubiczka S, Kropf S, Nickel I, Muschke P, Kleinstein J. Increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males. Fertil Steril. 2006Jan;85(1):135-8.
[53]Jiang MC, Lien YR, Chen SU, Ko TM, Ho HN, Yang YS. Transmission of de novo mutations of the deleted in azoospermia genes from a severely oligozoospermic male to a son via intracytoplasmic sperm injection. Fertil Steril.1999 Jun;71(6):1029-32.
[54]Mulhall JP, Reijo R, Alagappan R, Brown L, Page D, Carson R, Oates RD. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod.1997 Mar;12(3):503-8.
[55]Foresta C, Moro E, Ferlin A. Prognostic value of Y deletion analysis. The role of current methods. Hum Reprod.2001 Aug; 16(8):1543-7.
[1]Trifunovic A, Wredenberg A, Falkenberg M, et al Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature,2004,429:417-23.
[2]Spelbrink JN, Toivonen JM, Hakkaart GA, et al In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem, 2000,275:24818-28.
[3]Longley MJ, Ropp PA, Lim SE, el al Characterization of the native and recombinant catalytic subunit of human DNA polymerase gamma:identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity. Biochemistry.1998,37:10529-39.
[4]Kunkel TA, Soni A. Exonucleolytic proofreading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma. J Biol Chem,1988,263:4450-9.
[5]Graziewicz MA, Longley MJ, Bienstock RJ, et al Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol,2004,11:770-6.
[6]Ponamarev MV, Longley MJ, Nguyen D, et al Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis. J Biol Chem,2002,277:15225-8.
[7]Mancuso M, Filosto M, Oh SJ, et al A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol,2004,61:1777-9.
[8]Naviaux RK, Nguyen KV. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol,2005,58:491.
[9]Naviaux RK, Nyhan WL, Barshop BA, et al. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann Neurol,1999,45:54-8.
[10]Naviaux RK, Nguyen KV. POLG mutations associated with Alpers'syndrome and mitochondrial DNA depletion. Ann Neurol,2004,55:706-12.
[11]Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics,1996,36:449-58.
[12]Rovio AT, Abel J, Ahola AL, el al. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mamm Genome,2004,15:492-502.
[13]Rovio AT, Marchington DR, Donat S, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet,2001,29:261-2.
[14]Jensen M, Leffers H, Petersen JH, et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod,2004,19:65-70.
[15]Brusco A, Michielotto C, Gatta V, et al. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest,2006,29:1-4.
[16]Krausz C, Guarducci E, Becherini L, et al. The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab,2004,89:4292-7.
[17]Aknin-Seifer IE, Touraine RL, Lejeune H, et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod,2005,20:736-40.
[18]Rani DS, Carlus SJ, Poongothai J, et al. CAG repeat variation in the mtDNA polymerase gamma is not associated with oligoasthenozoospermia. Int J Androl,2008.
[19]Rovio A, Tiranti V, Bednarz AL, et al. Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals. Eur J Hum Genet,1999,7:140-6.
[20]Malyarchuk BA, Papuga M, Grzybowski T, et al. Low variability of the POLG (CAG)n repeat in north Eurasian populations. Hum Biol,2005,77:355-65.
[21]Schapira AH. Mitochondrial disease. Lancet,2006,368:70-82.
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